Summary - Overall (PI: Michel Nussenzweig) Although Zika virus (ZIKV) infection typically leads to a mild disease, it produces grim consequences when it occurs during pregnancy. Vertical transmission can lead to fetal demise, microcephaly or other developmental aberrations in up to nearly half of the cases. ZIKV is a global challenge; according to the CDC, nearly 40% of the world population lives in regions inhabited by the mosquito vectors that are competent for ZIKV. Therefore, a vaccine is needed that is both safe and efficacious in preventing ZIKV infection. ZIKV is a flavivirus like dengue (DENV), which is responsible for severe human disease and mortality. There are 4 serotypes of DENV (DENV1-4) that are antigenically very similar to each other and to ZIKV. This similarity can confer cross-protection, but it may also be responsible for causing a severe hemorrhagic form of dengue when antibodies elicited in response to one of the serotypes are cross-reactive and non- or poorly neutralizing to another serotype. The cross-reactive antibodies are thought to form immune complexes that enhance the infection and the disease, a phenomenon that is referred to as Antibody Dependent Enhancement (ADE). In vitro and in vivo experiments support the view that the ADE extends to ZIKV. Thus, a desirable goal is to develop a ZIKV vaccine that selectively elicits antibodies to neutralizing epitopes of ZIKV, while at the same time avoiding those to other flaviviruses, including DENV, that are non-neutralizing and potentially enhancing. Doing so requires an understanding of the neutralizing antibody response to ZIKV and structural understanding of how these antibodies recognize ZIKV surface proteins. This Program Project builds upon an established collaboration between the Nussenzweig, Bjorkman, and Rice laboratories. Its ultimate goal is to discover and characterize a panel of neutralizing epitopes on the ZIKV surface, and to use this information to design and test candidate vaccines to elicit antibodies that selectively target such neutralizing epitopes. We propose two highly interrelated projects led by Drs. Michel Nussenzweig and Pamela Bjorkman, which will be supported by a Scientific Core led by Dr. Charles Rice, who will provide the expertise in virology. In Project 1, previously characterized samples from exceptional ZIKV responders will be used for neutralizing antibody discovery from memory B cells. Project 2 will characterize the antibodies and their epitopes structurally, and the information obtained will enable the rational design and production of candidate immunogens. The immunogens designed in Project 2 will be evaluated in Project 1 using wild type and genetically humanized mice for safety and efficacy in protection against ZIKV and DENV infection. Activities in both projects will be supported by the Virology and Administrative Cores. The proposed experiments aim at developing vaccine candidates for subsequent evaluation in non-human primates, and as such have significant translational potential.